A2b adenosine receptor antagonists

ABSTRACT

Disclosed are novel compounds that are A 2B  adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.

This application is a Continuation of U.S. patent application Ser. No.11/189,202, filed Jul. 25, 2005, which is a Continuation of U.S. patentapplication Ser. No. 10/431,167, filed May 6, 2003, now U.S. Pat. No.6,977,300, which is a Continuation in Part of U.S. Non-Provisionalpatent application Ser. No. 10/290,921, filed Nov. 8, 2002, now U.S.Pat. No. 6,825,349, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/348,222, filed Nov. 9, 2001 the completedisclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to A_(2B) adenosine receptor antagonists,and to their use in treating mammals for various disease states, such asgastrointestinal disorders, immunological disorders, neurologicaldisorders, and cardiovascular diseases due to both cellularhyperproliferation and apoptosis, and the like. The invention alsorelates to methods for the preparation of such compounds, and topharmaceutical compositions containing them.

BACKGROUND

Adenosine is a naturally occurring nucleoside, which exerts itsbiological effects by interacting with a family of adenosine receptorsknown as A₁, A_(2A), A_(2B), and A₃, all of which modulate importantphysiological processes. For example, A_(2A) adenosine receptorsmodulate coronary vasodilation, A_(2B) receptors have been implicated inmast cell activation, asthma, vasodilation, regulation of cell growth,intestinal function, and modulation of neurosecretion (See AdenosineA_(2B) Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistovet al., Trends Pharmacol Sci 19:148-153), and A₃ adenosine receptorsmodulate cell proliferation processes.

Adenosine A_(2B) receptors are ubiquitous, and regulate multiplebiological activities. For example, adenosine binds to A_(2B) receptorson endothelial cells, thereby stimulating angiogenesis. Adenosine alsoregulates the growth of smooth muscle cell populations in blood vessels.Adenosine stimulates A_(2B) receptors on mast cells, thus modulatingType I hypersensitivity reactions. Adenosine also stimulatesgastrosecretory activity by ligation with A_(2B) in the intestine.

While many of these biological effects of adenosine are necessary tomaintain normal tissue homeostasis, under certain physiological changesit is desirable to modulate its effects. For example, the binding ofA_(2B) receptors stimulates angiogenesis by promoting the growth ofendothelial cells. Such activity is necessary in healing wounds, but thehyperproliferation of endothelial cells promotes diabetic retinopathy.Also, an undesirable increase in blood vessels occurs in neoplasia.Accordingly, inhibition of the binding of adenosine to A_(2B) receptorsin the endothelium will alleviate or prevent hypervasculation, thuspreventing retinopathy and inhibibiting tumor formation.

A_(2B) receptors are found in the colon in the basolateral domains ofintestinal epithelial cells, and when acted upon by the appropriateligand act to increase chloride secretion, thus causing diarrhea, whichis a common and potentially fatal complication of infectious diseasessuch as cholera and typhus. A_(2B) antagonists can therefore be used toblock intestinal chloride secretion, and are thus useful in thetreatment of inflammatory gastrointestinal tract disorders, includingdiarrhea.

Insensitivity to insulin exacerbates diabetes and obesity. Insulinsensitivity is decreased by the interaction of adenosine with A_(2B)receptors. Thus, blocking the adenosine A_(2B) receptors of individualswith diabetes or obesity would benefit patients with these disorders. Ithas also been demonstrated that A_(2B)-antagonists cause a reduction ofblood glucose levels, and thus would be particularly useful in thetreatment of type-II diabetes.

Another adverse biological effect of adenosine acting at the A_(2B)receptor is the over-stimulation of cerebral IL-6, a cytokine associatedwith dementias and Altheimer's disease. Inhibiting the binding ofadenosine to A_(2B) receptors would therefore mitigate thoseneurological disorders that are produced by IL-6.

Type I hypersensitivity disorders, such as asthma, hay fever, and atopiceczema, are stimulated by binding to A_(2B)-receptors of mast cells.Therefore, blocking these adenosine receptors would provide atherapeutic benefit against such disorders.

There are several compounds presently used in the treatment of asthma.For example, theophylline is an effective antiasthmatic agent, eventhough it is a poor adenosine receptor antagonist. However, considerableplasma levels are needed for it to be effective. Additionally,theophylline has substantial side effects, most of which are due to itsCNS action, which provide no beneficial effects in asthma, and to thefact that it non-specifically blocks all adenosine receptor subtypes.

Additionally adenosine treatment, such as inhaled adenosine (oradenosine monophosphate), provokes bronchoconstriction in asthmatics,but not in the normal population. This process is known to involve mastcell activation, in that it releases mast cell mediators, includinghistamine, PGD2-β-hexosaminidase and tryptase, and because it can beblocked by specific histamine H₁ blockers and chromolyn sodium.Accordingly, there is an intrinsic difference in the way adenosineinteracts with mast cells from asthmatics, and thus A_(2B) antagonistsare particularly useful in modulating mast cell function or in theactivation of human lung cells.

Accordingly, it is desired to provide compounds that are potent A_(2B)antagonists (i.e., compounds that inhibit the A_(2B) adenosinereceptor), fully or partially selective for the A_(2B) receptor, usefulin the treatment of various disease states related to modulation of theA_(2B) receptor, for example cancer, asthma and diarrhea.

SUMMARY OF THE INVENTION

It is an object of this invention to provide A_(2B) receptorantagonists. Accordingly, in a first aspect, the invention relates tocompounds of Formula I and Formula II:

wherein:

-   R¹ and R² are independently chosen from hydrogen, optionally    substituted alkyl, or a group -D-E, in which D is a covalent bond or    alkylene, and E is optionally substituted alkoxy, optionally    substituted cycloalkyl, optionally substituted aryl, optionally    substituted heteroaryl, optionally substituted heterocyclyl,    optionally substituted alkenyl or optionally substituted alkynyl,    with the proviso that when D is a covalent bond E cannot be alkoxy;-   R³ is hydrogen, optionally substituted alkyl or optionally    substituted cycloalkyl;-   X is optionally substituted arylene or optionally substituted    heteroarylene;-   Y is a covalent bond or alkylene in which one carbon atom can be    optionally replaced by —O—, —S—, or —NH—, and is optionally    substituted by hydroxy, alkoxy, optionally substituted amino, or    —COR, in which R is hydroxy, alkoxy or amino;-   with the proviso that when the optional substitution is hydroxy or    amino it cannot be adjacent to a heteroatom; and-   Z is optionally substituted monocyclic aryl or optionally    substituted monocyclic heteroaryl; or-   Z is hydrogen when X is optionally substituted heteroarylene and Y    is a covalent bond; with the proviso that when X is optionally    substituted arylene, Z is optionally substituted monocyclic    heteroaryl.

A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I or Formula II, or a mixture thereof, and at leastone pharmaceutically acceptable excipient.

A third aspect of this invention relates to a method of using thecompounds of Formula I and Formula II in the treatment of a disease orcondition in a mammal that is amenable to treatment with an A_(2B)receptor antagonist (i.e., inhibiting an adenosine receptorcharacterized as A_(2B)), comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of Formula I orFormula II, or a mixture thereof. Such diseases include, but are notlimited to, at least one of asthma, inflammatory gastrointestinal tractdisorders, including diarrhea, cardiovascular diseases such asatherosclerosis, neurological disorders such as senile dementia,Alzheimer's disease, and Parkinson's disease, and diseases related toangiogenesis, for example diabetic retinopathy and cancer.

A fourth aspect of this invention relates to methods for preparing thecompounds of Formula I and Formula II.

One preferred group of compounds of Formula I and II are those in whichR¹ and R² are independently hydrogen, optionally substituted loweralkyl, or a group -D-E, in which D is a covalent bond or alkylene, and Eis optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted alkenyl, or optionally substituted alkynyl,particularly those in which R³ is hydrogen.

Within this group, a first preferred class of compounds include those inwhich R¹ and R² are independently lower alkyl optionally substituted bycycloalkyl, preferably n-propyl, and X is optionally substitutedphenylene. Within this class, a preferred subclass of compounds arethose in which Y is alkylene, including alkylene in which a carbon atomis replaced by oxygen, preferably —O—CH₂—, more especially where theoxygen is the point of attachment to phenylene. Within this subclass, itis preferred that Z is optionally substituted oxadiazole, particularlyoptionally substituted [1,2,4]-oxadiazol-3-yl, especially[1,2,4]-oxadiazol-3-yl substituted by optionally substituted phenyl oroptionally substituted pyridyl.

A second preferred class of compounds include those in which X isoptionally substituted 1,4-pyrazolene. Within this class, a preferredsubclass of compounds are those in which Y is a covalent bond oralkylene, especially lower alkylene, and Z is hydrogen, optionallysubstituted phenyl, optionally substituted pyridyl, or optionallysubstituted oxadiazole. Within this subclass, one preferred embodimentincludes compounds in which R¹ is lower alkyl optionally substituted bycycloalkyl, and R² is hydrogen.

A more preferred embodiment includes those compounds in which Y is—(CH₂)— or —CH(CH₃)— and Z is optionally substituted phenyl, or Y is—(CH₂)— or —CH(CH₃)— and Z is optionally substituted oxadiazole,particularly 3,5-[1,2,4]-oxadiazole, or Y is —(CH₂)— or —CH(CH₃)— and Zis optionally substituted pyridyl. Within this subclass, also preferredare those compounds in which R¹ and R² are independently lower alkyloptionally substituted by cycloalkyl, especially n-propyl. Morepreferred are those compounds in which Y is a covalent bond, —(CH₂)— or—CH(CH₃)— and Z is hydrogen, optionally substituted phenyl, oroptionally substituted pyridyl, particularly where Y is a covalent bondand Z is hydrogen.

At present, the preferred compounds are:

-   1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-methyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic    acid;-   8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.-   1-(cyclopropylmethyl)-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-n-butyl-8-[1-(6-trifluoromethylpyridin-3-ylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}benzoic    acid;-   1,3-dipropyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   6-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}pyridine-2-carboxylic    acid;-   3-ethyl-1-propyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-3-ethyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;    and-   3-ethyl-1-(2-methylpropyl)-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.

DEFINITIONS AND GENERAL PARAMETERS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5    substituents, preferably 1 to 3 substituents, selected from the    group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl,    cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,    alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,    thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,    heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,    aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,    heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,    —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl.    Unless otherwise constrained by the definition, all substituents may    optionally be further substituted by 1, 2, or 3 substituents chosen    from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,    halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R, where    R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   2) an alkyl group as defined above that is interrupted by 1-10 atoms    independently chosen from oxygen, sulfur and NR_(a)—, where R_(a) is    chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,    alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be    optionally further substituted by alkyl, alkoxy, halogen, CF₃,    amino, substituted amino, cyano, or —S(O)_(n)R, in which R is alkyl,    aryl, or heteroaryl and n is 0, 1 or 2; or-   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5    substituents as defined above and is also interrupted by 1-10 atoms    as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms.This term is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents, preferably 1, 2, or 3 substituents, asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substitutedalkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1, 2, 3,4, or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This termis exemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

The term “substituted alkylene” refers to:

-   (1) an alkylene group as defined above having 1, 2, 3, 4, or 5    substituents selected from the group consisting of alkyl, alkenyl,    alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,    amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,    hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,    heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,    heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,    heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,    —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and    —SO₂-heteroaryl. Unless otherwise constrained by the definition, all    substituents may optionally be further substituted by 1, 2, or 3    substituents chosen from alkyl, carboxy, carboxyalkyl,    aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted    amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl    and n is 0, 1 or 2; or-   (2) an alkylene group as defined above that is interrupted by 1-20    atoms independently chosen from oxygen, sulfur and NR_(a)—, where    R_(a) is chosen from hydrogen, optionally substituted alkyl,    cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or    groups selected from carbonyl, carboxyester, carboxyamide and    sulfonyl; or-   (3) an alkylene group as defined above that has both 1, 2, 3, 4 or 5    substituents as defined above and is also interrupted by 1-20 atoms    as defined above. Examples of substituted alkylenes are    chloromethylene (—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—),    methylaminoethylene (—CH(NHMe)CH₂—), 2-carboxypropylene    isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),    ethylmethylaminoethyl (—CH₂CH₂N(CH₃)CH₂CH₂—),    1-ethoxy-2-(2-ethoxy-ethoxy)ethane    (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups areoptionally substituted alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 20 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl).Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂), 1-propyleneor allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or prop-1-yn-3-yl, —CH₂C≡CH), and the like. In theevent that alkynyl is attached to nitrogen, the triple bond cannot bealpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or whereboth R groups are joined to form a heterocyclic group (e.g.,morpholino). Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl,—O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may beoptionally further substituted by alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, or —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

The term “arylene” refers to a diradical of an aryl group as definedabove. This term is exemplified by groups such as 1,4-phenylene,1,3-phenylene, 1,2-phenylene, 1,4′-biphenylene, and the like.

Unless otherwise constrained by the definition for the aryl or arylenesubstituent, such aryl or arylene groups can optionally be substitutedwith from 1 to 5 substituents, preferably 1 to 3 substituents, selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂. The term “substituted amino”refers to the group —NRR where each R is independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (forexample, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl providedthat both R groups are not hydrogen, or a group —Y-Z, in which Y isoptionally substituted alkylene and Z is alkenyl, cycloalkenyl, oralkynyl, Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or

—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to carbocyclic groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl,bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to whichis fused an aryl group, for example indane, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to a radical derived from an aromaticcyclic group (i.e., fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or 4 heteroatomsselected from oxygen, nitrogen and sulfur within at least one ring. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl, benzothiazolyl, orbenzothienyl). Examples of heteroaryls include, but are not limited to,[1,2,4]oxadiazole, [1,3,4]oxadiazole, [1,2,4]thiadiazole,[1,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, andthe like as well as N-oxide and N-alkoxy derivatives of nitrogencontaining heteroaryl compounds, for example pyridine-N-oxidederivatives.

The term “heteroarylene” refers to a diradical of a heteroaryl group asdefined above. This term is exemplified by groups such as2,5-imidazolene, 3,5-[1,2,4]oxadiazolene, 2,4-oxazolene, 1,4-pyrazolene,and the like. For example, 1,4-pyrazolene is:

where A represents the point of attachment.

Unless otherwise constrained by the definition for the heteroaryl orheteroarylene substituent, such heteroaryl or heterarylene groups can beoptionally substituted with 1 to 5 substituents, preferably 1 to 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “heteroaralkyl” refers to a heteroaryl group covalently linkedto an alkylene group, where heteroaryl and alkylene are defined herein.“Optionally substituted heteroaralkyl” refers to an optionallysubstituted heteroaryl group covalently linked to an optionallysubstituted alkylene group. Such heteroaralkyl groups are exemplified by3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, andthe like.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated or partiallyunsaturated group having a single ring or multiple condensed rings,having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring. Heterocyclic groups can havea single ring or multiple condensed rings, and includetetrahydrofuranyl, morpholino, piperidinyl, piperazino, dihydropyridino,and the like.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfone” refers to a group —S(O)₂R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” refersto a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “compound of Formula I and Formula II” is intended to encompassthe compounds of the invention as disclosed, and the pharmaceuticallyacceptable salts, pharmaceutically acceptable esters, prodrugs, hydratesand polymorphs of such compounds. Additionally, the compounds of theinvention may possess one or more asymmetric centers, and can beproduced as a racemic mixture or as individual enantiomers ordiastereoisomers. The number of stereoisomers present in any givencompound of Formula I depends upon the number of asymmetric centerspresent (there are 2^(n) stereoisomers possible where n is the number ofasymmetric centers). The individual stereoisomers may be obtained byresolving a racemic or non-racemic mixture of an intermediate at someappropriate stage of the synthesis, or by resolution of the compound ofFormula I by conventional means. The individual stereoisomers (includingindividual enantiomers and diastereoisomers) as well as racemic andnon-racemic mixtures of stereoisomers are encompassed within the scopeof the present invention, all of which are intended to be depicted bythe structures of this specification unless otherwise specificallyindicated.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When the compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) which they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

Nomenclature

The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which R¹ isn-propyl, R² is n-propyl, R³ is hydrogen, X is phenylene, Y is —O—(CH₂),and Z is 5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-yl,

which is named:

-   8-{4-[5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent” or “inert solvent” mean asolvent inert under the conditions of the reaction being described inconjunction therewith [including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like]. Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I where R¹ and R² are the same, R³ is hydrogen,and Y includes an oxygen, sulfur or nitrogen atom may be prepared asshown in Reaction Scheme I.

where Bz is benzyl, Boc is t-butyloxycarbonyl, and L is —O—, —S—, or—NH—.

Note that when R³ is hydrogen, Formula I and II are the same compound asa consequence of tautomerism.

Step 1—Preparation of Formula (2)

The compound of formula (1), which is protected at the N-7 position, iscommercially available, or may be prepared by means well known in theart (see, for example, Synthetic Communications, 20(16), 2459-2467(1990)). The compound of formula (1) is reacted with at least twoequivalents of a compound of formula R¹LG, where LG is a leaving group,preferably chlorine, bromine, or iodine, in the presence of a strongbase, for example sodium hydride. The reaction is carried out in a polarsolvent, for example DMF, initially at a temperature of about roomtemperature, followed by reaction at a temperature of about 30-100° C.,for example about 70° C., for about 6-24 hours. When the reaction issubstantially complete, the product of formula (2) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

It should be noted that this reaction only provides compounds of formula(2) in which R¹ and R² are the same. A procedure for preparing compoundsof formula (2) in which R¹ and R² are different is shown below inReaction Scheme III.

A different synthesis is required for the preparation of compounds offormula (2) in which R¹ and/or R² are aryl or heteroaryl groups, and isshown in Reaction Scheme III.

Step 2—Preparation of Formula (3)

The compound of formula (2) is then halogenated at the 8-position, togive a compound of formula (3), by reaction with a halogenating agent,for example N-chlorosuccinimide, to give the 8-chloro compound offormula (3). In general, the compound of formula (2) is dissolved in aninert solvent, for example tetrahydrofuran, and N-bromosuccinimide (orN-chlorosuccinimide) is added. The reaction is carried out at atemperature of about 0-30° C., for example about room temperature, forabout 1-10 hours, for example about 4 hours. When the reaction issubstantially complete, the product of formula (3) is isolated byconventional means, and recrystallized.

Step 3—Preparation of Formula (4)

The compound of formula (3) is then converted to a compound of formula(4) by reaction with an appropriately substituted boronic acidderivative in the presence of a palladium(0) complex. For example, whereX is optionally substituted phenyl, the compound of formula (3) isreacted with an optionally substituted phenylboronic acid. The reactionis carried out in an inert solvent, for example toluene/ethanol, in thepresence of aqueous sodium carbonate solution andtetrakis(triphenylphosphine)-palladium(0), at about reflux temperaturefor about 24 hours. When the reaction is substantially complete, theproduct of formula (4) is isolated by conventional means, for example byremoving the solvent under reduced pressure, followed by chromatographyof the residue on silica gel.

Step 4—Preparation of Formula (5) Part a)

The benzyl protecting group of the compound of formula (4) is thenreplaced by Boc, to give the compound of formula (5). In general, thecompound of formula (4) is dissolved in an inert solvent, for examplemethanol, and a hydrogenation catalyst added. The reaction is stirredunder an atmosphere of hydrogen, at a temperature of about 0-30° C., forexample about room temperature, for about 8-24 hours, for example about18 hours. When the reaction is substantially complete, the catalyst isremoved by filtration, and the product isolated by conventional means.

Part b)

The product is then dissolved in an inert solvent, for example methanol,to which was added an excess of di t-butyldicarbonate and a hinderedbase, for example ethyldiisopropylamine. The mixture is refluxed forabout 8-24 hours, for example about 18 hours. When the reaction issubstantially complete, the catalyst is removed by filtration, and thecompound of formula (5) isolated by conventional means, for example byremoving the solvent under reduced pressure, followed by chromatographyof the residue on silica gel.

Step 5—Preparation of Formula I where R³ is Hydrogen

The compound of formula (5) is then converted to a compound of Formula Iby reaction with a compound of the formula Z-Y-LG, where Z and Y are asdefined above and LG is a leaving group, preferably a halogen, morepreferably chloro (the Boc protecting group is removed simultaneously).The reaction is carried out in the presence of a strong base, forexample sodium hydride, in an inert polar solvent, preferably DMF, at atemperature of about 0-30° C., preferably about room temperature, forabout 8-24 hours, preferably about 16 hours. The BOC protecting group isalso removed in this reaction sequence. When the reaction issubstantially complete, the product of Formula I where R³ is hydrogen isisolated by conventional means, for example by chromatography on silicagel.

Step 5—Preparation of Formula I where R³ is other than Hydrogen

A compound of Formula I in which R³ is hydrogen may be converted to acompound of Formula I in which R³ is not hydrogen by reaction with acompound of formula R³-LG, where LG is a leaving group, preferably iodoor bromo. The reaction is carried out in the presence of a mild base,for example potassium carbonate, in an inert polar solvent, preferablyDMF, at a temperature of about 30-100° C., preferably about 70° C., forabout 8-24 hours, preferably about 16 hours. When the reaction issubstantially complete, the product of Formula I where R³ is other thanhydrogen is isolated by conventional means, for example bychromatography on silica gel.

Alternatively, the benzyl protecting group of formula (4) may bereplaced by a trimethylsilyl-ethoxymethyl protecting group (instead of aBOC group), the subsequent removal of which can be accomplished undermilder reaction conditions. In general, the product of Step 4a isdissolved in an inert solvent, preferably anhydrous DMF (100 mL), andreacted with trimethylsilyl-ethoxymethyl chloride in the presence of abase, preferably potassium carbonate. The reaction is conducted at atemperature of about 50-90° C., preferably about 70° C., for about 1-6days, preferably about 72 hours. When the reaction is substantiallycomplete, the catalyst is removed by filtration, and the productisolated by conventional means, preferably flash chromatography.

The product is then reacted with Z-Y-LG, where Z and Y are as definedabove and LG is a leaving group, as shown in step 5 above. Thetrimethylsilyl-ethoxymethyl protecting group is removed from theresulting intermediate compound by treatment by acid in a proticsolvent, preferably hydrochloric acid in ethanol, to give a compound ofFormula I.

Alternatively, the benzyl group of the starting material of formula (1)can be replaced by BOC before the halogenation of step 2. In thismanner, there is no need to change the protecting group from benzyl toBOC as outlined above in step 4.

An alternative method for preparing the compounds of Formula I where R³is hydrogen, Z is an optionally substituted 1,2,4-oxadiazole, andpreferably Y is oxygen, is shown in Reaction Scheme II.

Step 1—Preparation of Formula (7)

The compound of formula (6) is prepared in a manner similar to thatshown above for compound (4). It is deprotected by treatment withhydrogen in the presence of a catalyst, preferably Pd on carbon. Thehydroxy compound thus produced is reacted with tert-butyldimethylsilylchloride in the presence of imidazole to give thetert-butyldimethylsilyloxy derivative. This compound is reacted withsodium hydride, and the anion thus produced is reacted withbenzyloxymethyl chloride to provide a compound that is protected at theN-7 position by benzyloxymethyl. The tert-butyldimethylsilyl protectinggroup is then removed by the usual means, for example treatment withtetrabutylammonium fluoride, and the resulting hydroxy compound isreacted with iodoacetonitrile or chloroacetonitrile, in the presence ofa strong base, for example potassium t-butoxide. The reaction is carriedout in an inert solvent, preferably tetrahydrofuran at about roomtemperature, for about 6-24 hours. When the reaction is substantiallycomplete, the product of formula (7) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography of the residue on silica gel.

Step 2—Preparation of Formula (8)

The compound of formula (7) is then reacted with hydroxylaminehydrochloride. In general, the compound of formula (7) is dissolved inan inert solvent, for example ethanol, and hydroxylamine hydrochlorideis added, along with an equivalent amount of a strong base, for examplesodium ethoxide. The reaction is carried out at a temperature of about0-30° C., for example about room temperature, for about 6-24 hours. Whenthe reaction is substantially complete, the product of formula (8) isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel.

Step 3—Preparation of Formula I

The compound of formula (8) is then cyclized to an optionallysubstituted 1,2,4-oxadiazole of Formula I by reaction with anappropriately substituted acid chloride of formula RC(O)Cl, in which Rrepresents an optional substitution that leads to 5-substitution on theoxadiazole ring. In general, the compound of formula (8) is dissolved inan inert solvent, for example dioxane, and potassium carbonate and theacid chloride added. The mixture is allowed to react for about 10minutes at a temperature of about 0-30° C., preferably about roomtemperature. When the reaction is substantially complete, theintermediate is isolated conventionally, and dissolved in a high boilinginert solvent, for example xylene. The mixture is reacted for about 6-24hours, at a temperature of about 100-160° C., preferably about 145° C.The product of Formula I is isolated by conventional means, for exampleby removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

A method for preparing compounds of Formula I in which R¹ and R² are notthe same is shown in Reaction Scheme III.

where R¹ and R² are as defined above, Bz is benzyl, and Hal is chloro,bromo, or iodo.

In general, the procedure is carried out as described in SyntheticCommunications, 20(16), 2459-2467 (1990). The reaction scheme takesadvantage of the fact that xanthines are well known to react withalkylating agents in the order N3>N7>N1. With N7 protected, as in thecompound of formula (1), reaction with a compound of formula R²LG, whereLG is a leaving group, preferably chlorine, bromine, or iodine, with aslight excess of R²LG in the same manner as shown above for thepreparation of a compound of formula (2) provides the compound offormula (9). Further reaction of (9) with a compound of formula R¹LGprovides the compound of formula (10) in which R¹ and R² are different.

A method for preparing compounds of formula (2) in which R² is hydrogenor alkyl and R¹ is aryl or heteroaryl is shown in Reaction Scheme IV.

The compounds of formula (2) in which R¹ is aryl or heteroaryl may beprepared as described in Synthesis, 1995, p855-858. In general, acompound of formula (11), prepared by means well known in the art, isreacted with an appropriately substituted isocyanate of formula R¹NCO toprovide a compound of formula (12), which is cyclized under basicconditions, for example treatment with sodium ethoxide, to provide acompound of formula (2) in which R¹ is aryl or heteroaryl and R² ishydrogen. This method can also be used to provide compounds in which R¹is alkyl etc.

The compound of formula (2) in which R² is hydrogen can then be furtherreacted with an alkyl halide of formula R²hal in the same manner asshown in Reaction Scheme I to provide a compound of formula (2) in whichR¹ is aryl or heteroaryl and R² is alkyl.

Compounds of formula (2) in which R¹ and R² are both aryl or heteroarylare prepared as shown in Chem. Ber., GE; 111; 1978; 982-995.

A method for preparing compounds of Formula I in which R³ is nothydrogen is shown in Reaction Scheme V.

Preparation of Formula (13)

The benzyl protecting group of the compound of formula (2) is removed byhydrogenation as described in Reaction Scheme I, step 4. The resultingcompound is then reacted with a compound of formula R³LG, where LG is aleaving group, preferably chlorine, bromine, or iodine, in the presenceof a base, for example potassium carbonate. The reaction is carried outin a polar solvent, for example DMF, initially at a temperature of aboutroom temperature, followed by reaction at a temperature of about 30-100°C., for example about 70° C., for about 6-24 hours. When the reaction issubstantially complete, the product of formula (13) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

The reaction is disclosed in more detail in J. Med. Chem., 1999, 42,2527-2534.

An alternative method for preparing compounds of Formula I is shown inReaction Scheme VI. Coupling of the 8-chloro derivative of formula (14)with a compound of formula (HO)₂B—X—Y-Z is a convenient method forproviding compounds of Formula I without a heteroatom in the chain.

Preparation of a Compound of Formula II

The preparation of a compound of Formula II is carried out in the samemanner as shown above in Reaction Scheme I, II and III, starting with acompound of the formula (18), the preparation of which is shown inReaction Scheme VII

Similar reaction sequences are disclosed in U.S. Pat. No. 5,631,260, thecomplete disclosure of which is hereby incorporated by reference.

It should be noted that if RCO₂H (or RCOCl) is used in place of formicacid, a compound of formula (18) that is substituted at the 8-positionby R will result. Thus, if RCO₂H is equivalent to ZYXCO₂H (a compound offormula (22)), an alternative synthesis of a compound of Formula II canbe accomplished, as shown in Reaction Scheme VIII.

It should be noted that if R³ is hydrogen, a compound of Formula I or IIis produced.

The compound of formula (19) is commercially available, or is preparedby means well known in the art. It is converted into a compound ofFormula II (or a compound of Formula I when R³ is hydrogen) as describedin U.S. Pat. No. 5,446,046, the complete disclosure of which is herebyincorporated by reference.

The compound of formula (21) in which R³ is hydrogen may be purchasedfrom a commercial source, for example 5,6-diamino-1,3-dipropyluracil, orprepared by means well known in the art.

A similar reaction can be carried out starting with a nitroso aminoderivative of the formula (24).

Reduction of the compound of formula (24) with hydrogen/platinum oxidecatalyst provides the corresponding diamino compound (21) in which R³ ishydrogen. Alternatively, the compound of formula (24) can be firstsubstituted with R³ as described in Reaction Scheme VII above, toprovide the corresponding diamino compound of formula (21) where R³ isother than hydrogen.

Alternatively, a compound of formula (24) in which R² is hydrogen and R¹is other than hydrogen can be converted to a compound of Formula I inwhich R² is hydrogen and R¹ is other than hydrogen as shown in ReactionScheme IX.

Step 1—Preparation of Formula (23)

The commercially available compound 6-aminouracil is first silylated,for example by reaction with hexamethyldisilazane as a solvent in thepresence of a catalyst, for example ammonium sulfate. The reaction iscarried out at about reflux temperature, for about 1-10 hours. When thereaction is substantially complete, the silylated compound thus producedis isolated conventionally, and then reacted with a compound of formulaR¹Hal, where R¹ is as defined above other than hydrogen, preferably inthe absence of a solvent. The reaction is carried out at about reflux,for about 12 hours to 7 days. When the reaction is substantiallycomplete, the product of formula (23) is isolated by conventional means.

Step 2—Preparation of Formula (24)

The compound of formula (23) is then dissolved in an aqueous acid, forexample aqueous acetic acid, and reacted with sodium nitrite. Thereaction is carried out at a temperature of about 20-50° C., preferablyabout 30° C., over about 30 minutes. When the reaction is substantiallycomplete, the product of formula (24) is isolated by conventional means,for example by filtration.

Step 3—Preparation of Formula (25)

The compound of formula (24) is then reduced to a diamino derivative. Ingeneral, the compound of formula (24) is dissolved in aqueous ammonia,and then a reducing agent, for example sodium hydrosulfite, added. Thereaction is conducted at a temperature of about 70° C. When the reactionis substantially complete, the product of formula (25) is isolatedconventionally, for example by filtration of the cooled reactionmixture.

Step 4—Preparation of Formula I

The compound of formula (25) is then reacted with a carboxylic acid ofthe formula Z-Y—X—CO₂H in the presence of a carbodiimide, for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction is conducted at a temperature of about 20-30° C., for about12-48 hours. The product is isolated conventionally, for example byfiltration, and reacted with excess hexamethyldisilazane in the presenceof ammonium sulfate, for about 2 days at reflux. When the reaction issubstantially complete, the product of Formula I is isolatedconventionally, for example by filtration of the cooled reactionmixture.

A specific example of the preparation shown in Reaction Scheme IX, whereX is optionally substituted 1,4-pyrazolene, is shown in Reaction SchemeX.

where SEM is 2,2-(trimethylsilyl)ethoxymethyl and halo is chloro, bromo,or iodo. It should be noted that the compound of formula (26)corresponds to a compound of Formula I in which R² and R³ are hydrogen,X is 1-pyrazol-4-yl, Y is methylene, and Z is phenyl. This reaction isdescribed in more detail in the following examples.

The same reaction scheme can be used for the preparation of a compoundof Formula I in which the 1 and 3 positions are substituted (i.e., R¹and R² are not hydrogen), by starting with a compound of formula (21) inwhich R³ is hydrogen and reacting with the compound of formula (22) asabove.

An example of a synthesis of a compound of formula (22) is shown inReaction Scheme XI:

For example, if Z-Y—Br represents 3-phenylpropyl bromide, then theproduct (22) is 1-(3-phenylpropyl)pyrazole-4-carboxylic acid. If Z-Y—Brrepresents (1-oxy-pyridin-3-yl)methyl bromide, then the product (22) is1-(1-oxypyridin-3-ylmethyl)pyrazole-4-carboxylic acid. The reaction iscarried out as shown in Example 9.

The pyrazole product of formula (22) is then reacted with a compound offormula (21) or (25) as described above, and in Example 9, to provide acompound of Formula II (and Formula I if R³ is hydrogen). For example:

The preparation of a compound of Formula I in which R¹ is hydrogen andR² is other than hydrogen from a compound of formula (24) is shown inReaction Scheme XII.

Step 1—Preparation of Formula (31)

The compound of formula (30) is either commercially available orprepared by means well known in the art. It is reacted with ethylcyanoacetate in a protic solvent, for example ethanol, in the presenceof a strong base, for example sodium ethoxide. The reaction is carriedout at about reflux temperature, for about 4 to about 24 hours. When thereaction is substantially complete, the compound of formula (31) thusproduced is isolated conventionally.

Step 2—Preparation of Formula (24)

The compound of formula (31) is then mixed with sodium nitrite in anaqueous solvent, for example dimethylformamide and water, and reactedwith a strong acid, for example hydrochloric acid, to produce thenitroso compound of formula (24). The reaction is carried out at atemperature of about 50° C. to about 100° C., for about 1 hour. When thereaction is substantially complete, the product of formula (24) isisolated by conventional means.

Step 3—Preparation of Formula (21)

The compound of formula (24) is then reduced to a diamino derivative. Ingeneral, the compound of formula (24) is dissolved in aqueous ammonia,and then a reducing agent, for example sodium hydrosulfite, added. Thereaction is conducted at a temperature of about 70° C. When the reactionis substantially complete, the product of formula (21) is isolatedconventionally, for example by filtration of the cooled reactionmixture.

Step 4—Preparation of Formula I

The compound of formula (21) is then reacted with a carboxylic acid ofthe formula Z-Y—X—CO₂H in the same manner as described for ReactionScheme IX, step 4, to produce a compound of Formula I.

The compound of formula (31) can be used in an alternative synthesis toprepare a compound of Formula I in which R¹ is hydrogen and R² is otherthan hydrogen, or both R¹ and R² are other than hydrogen and are thesame or different, as shown in Reaction Scheme XIII.

Steps 1 and 2

The compound of formula (31), prepared as shown above, is reacted withthe dimethylacetal of N,N-dimethylformamide in a polar solvent, forexample N,N-dimethylformamide. The reaction is carried out at about 40°C., for about 1 hour. When the reaction is substantially complete, thecompound of formula (32) thus produced is reacted with a compound offormula R¹Hal, where Hal is chloro, bromo, or iodo, in the presence of abase, for example potassium carbonate. The reaction is carried out atabout 80° C., for about 4-24 hour. When the reaction is substantiallycomplete, the product of formula (33) is isolated conventionally, forexample by evaporation of the solvents under reduced pressure, and theresidue is used in the next reaction with no further purification.

Step 2

The compound of formula (33) is reacted with aqueous ammonia in a polarsolvent, for example suspended in methanol. The reaction is carried outat about room temperature, for about 1-3 days. When the reaction issubstantially complete, the product of formula (33) is isolatedconventionally, for example by evaporation of the solvents under reducedpressure, and triturating the residue with water.

The compound of formula (34) is then converted to a compound of FormulaI in the same manner as shown above for the preparation of the compoundof formula (23) in Reaction Scheme IX.

Preferred Processes and Last Steps

The compounds of the present invention can be prepared according to thefollowing last steps:

1. Contacting a compound of the formula:

in which R¹, R², and X are as defined in the Summary of the Invention, Lis —O—. —S—, or —NH—, and Boc is t-butyloxycarbonyl; with a compound ofthe formula Z-Y-LG, in which Z and Y are as defined in the Summary ofthe Invention, and LG is a leaving group.

2. Contacting a compound of the formula:

in which R¹, R², and X, Y and Z are as defined in the Summary of theInvention: with a compound of the formula R³-LG, where R³ is as definedin the Summary of the Invention, and LG is a leaving group.

3. Contacting a compound of the formula:

in which R¹, R², and X are as defined in the Summary of the Invention:with an acid chloride of the formula RC(O)Cl, in which R represents anoptional substitution that leads to 5-substitution on the oxadiazolering; to provide a compound of Formula I in which Y is oxygen, and Z isoptionally substituted 1,2,4-oxadiazole.

4. Contacting a compound of the formula:

in which R¹, R², and R³ are as defined in the Summary of the Invention:with a compound of formula (HO)₂B—X—Y-Z, in which X, Y and Z are asdefined in the Summary of the Invention.

5. Contacting a compound of the formula:

in which R¹, R², and R³ are as defined in the Summary of the Invention:with a compound of the formula ZYXCO₂H (a compound of formula (22)), inwhich X, Y and Z are as defined in the Summary of the Invention.

Utility, Testing and Administration General Utility

The compounds of Formula I and II are effective in the treatment ofconditions that respond to administration of A_(2B) adenosine receptorantagonists. Such conditions include, but are not limited to, at leastone of diarrhea, atherosclerosis, restenosis, diabetes, in particulartype-II diabetes, macular degeneration, diabetic retinopathy, cancer,senile dementia, Alzheimer's disease, Parkinson's disease, traumaticbrain injury, and Type I hypersensitivity reactions, including asthma,atopic eczema, and hay fever.

Testing

Activity testing is conducted as described in those patents and patentapplications referenced above, and in the Examples below, and by methodsapparent to one skilled in the art.

Pharmaceutical Compositions

The compounds of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

Administration

The compounds of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parental, particularly by injection. Theforms in which the novel compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof Formula I in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of the compoundsof Formula I. Administration may be via capsule or enteric coatedtablets, or the like. In making the pharmaceutical compositions thatinclude at least one compound of Formula I, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, in can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds of Formula I are effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 10mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg,and for parenteral administration, preferably from 10 to 700 mg of acompound of Formula I, more preferably about 50-200 mg. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Preparation of a Compound of Formula (2) Preparation of aCompound of Formula (2) where R¹ and R² are Both n-Propyl

To a solution of 7-benzyl-1,3,7-trihydropurine-2,6-dione (6.4 g, 26.4mmol), the compound of formula (1), in N,N-dimethylformamide (200 ml) atroom temperature was added sodium hydride (2.6 g, 66 mmol). The mixturewas stirred for 20 minutes, then iodopropane (6.5 ml, 66 mmol) added,and stirred at room temperature for 3 hours. The mixture was then heatedto 70° C. and stirred overnight. The solvent was removed under reducedpressure, dissolved in dichloromethane, and passed through a silica gelplug, washing with 1:1 hexane/ethyl acetate. The solvent was removedunder reduced pressure, affording crude7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione (8.5 g, 98% yield),which was used in the next reaction with no further purification.

B. Preparation of a Compound of Formula (2), Varying R¹ and R²

Similarly, following the procedure of 1A above, but replacingiodopropane by other halides, the following compounds of formula (3) areprepared:

-   7-benzyl-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;-   1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;    and-   7-benzyl-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 2 Preparation of a Compound of Formula (3) A. Preparation of aCompound of Formula (3) where R¹ and R² are both n-Propyl

7-Benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, a compound offormula (2), (2.0 g, 6.1 mmole) and N-chlorosuccinimide (1.0 g, 7.4mmole) were combined in 100 mL of tetrahydrofuran and stirred at roomtemperature for 4 hours. The solvent was removed under reduced pressure,and the residue dissolved in ethyl acetate. The solution was washed withwater, then brine, and dried over magnesium sulfate. The solvent wasremoved under vacuum, to afford a compound of formula (3) where R¹ andR² are both n-propyl,7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, which wasrecrystallized from ethyl acetate/hexane (1:50).

B. Preparation of a Compound of Formula (3), Varying R¹ and R²

Similarly, following the procedure of 2A above, but replacing7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione by other compoundsof formula (2), the following compounds of formula (3) are prepared:

-   7-benzyl-8-chloro-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;-   8-chloro-1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-chloro-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;    and-   7-benzyl-8-chloro-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

C. Preparation of a Compound of Formula (3), Varying R¹ and R²

Similarly, following the procedure of 2A above, but replacing7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione by other compoundsof formula (2), any compound of formula (3) is prepared.

EXAMPLE 3 Preparation of a Compound of Formula (4) A. Preparation of aCompound of Formula (4) where R¹ and R² are both n-Propyl, X is Phenyl,and L is —O—

7-Benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, acompound of formula (3) where R¹ and R² are both n-propyl (5.0 g, 14mmoles), and 4-hydroxyphenyl-boronic acid (2.0 g, 14 mmoles) weredissolved in 100 ml of a mixture of toluene/ethanol (4:1) and stirred atreflux for 16 hours. Solvent was removed under reduced pressure, and theresidue was chromatographed over a silica gel column, eluting with ethylacetate:hexane (1:4) to give a compound of formula (4) where R¹ and R²are both n-propyl, X is phenyl, and L is —O—(7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione),as a pale yellow solid.

B. Preparation of a Compound of Formula (4), Varying R¹, R², X and L

Similarly, following the procedure of 3A above, replacing7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione with othercompounds of formula (3), the following compounds of formula (4) areprepared:

-   7-benzyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(3-hydroxypyrid-2-yl)-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;-   8-(2-fluoro-3-hydroxyphenyl)-1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(5-hydroxybenzothiazol-2-yl)-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;    and-   7-benzyl-8-(4-hydroxyphenyl)-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

C. Preparation of a Compound of Formula (4), Varying R¹, R², X and L

Similarly, following the procedure of 3A above, but replacing7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione with othercompounds of formula (3), any compound of formula (4) is prepared.

EXAMPLE 4 Preparation of a Compound of Formula (5) A. Preparation of aCompound of Formula (5) where R¹ and R² are both n-Propyl, X is Phenyl,and L is —O—

The compound of formula (4) where R¹ and R² are both n-propyl, X isphenyl, and L is—O-(7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione)(613 mg) was dissolved in methanol (50 ml), a catalytic amount ofpalladium hydroxide added, and the mixture stirred under hydrogen atroom temperature overnight. The mixture was filtered, washing thecatalyst with methanol, and the solvent was evaporated from the filtrateunder reduced pressure to provide.8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine.

This product was dissolved in methanol, di-tert-butyldicarbonate (0.7 g,3.2 mmol) and N,N-di-isopropylethylamine (1 ml) added, and the mixturerefluxed overnight. The solvent was removed under reduced pressure, andthe residue chromatographed on a silica gel column, to give a compoundof formula (5),7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula (5), Varying R¹, R², X and L

Similarly, following the procedure of 4A above, replacing7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other compounds of formula (4), the following compounds of formula(5) are prepared:

-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(3-hydroxypyrid-2-yl)-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(2-fluoro-3-hydroxyphenyl)-1,3-dibenzyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(5-hydroxybenzothiazol-2-yl)-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;    and-   7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

C. Preparation of a Compound of Formula (5), Varying R¹, R³, and X

Similarly, following the procedure of 4A above, but replacing7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other compounds of formula (3), any compound of formula (5) isprepared.

EXAMPLE 5 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ and R² are n-Propyl, X is Phenyl, Y is—O—CH₂—, and Z is 5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-yl

A mixture of7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of formula (5) (50 mg, 0.117 mmol),3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole (26 mg, 0.117mmol), and sodium hydride (10 mg, 0.234 mmol) in N,N-dimethylformamidewas stirred at room temperature for 24 hours. The solvent was removedunder reduced pressure, and the residue purified by preparative thinlayer chromatography, to afford8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula I where R¹ and R² are n-Propyl,Varying X, Y, and Z

Similarly, following the procedure of 5A above, but optionally replacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula Cl-Y-Z, the following compounds of Formula I were prepared:

-   8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-(trifluoromethyl)phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   8-{4-[5-(4-trifluoromethylphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

C. Preparation of a Compound of Formula I, Varying R¹, R², X, Y, and Z

Similarly, following the procedure of 5A above, but optionally replacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula YZ, the following compounds of Formula I are prepared:

-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(2-fluoro-3-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dibenzyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(2-trifluoromethyl-4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di-(phenylethyl)-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-trifluoromethyl-3-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(furan-3-ylethyl)-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)imidazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)oxazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)thiazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-1,3,5-triazin-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)pyrimidin-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylpropoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-trifluoromethylphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(3,4-dimethoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   8-{5-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]pyridin-2-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

D. Preparation of a Compound of Formula I, Varying R¹, R², X, Y, and Z

Similarly, following the procedure of 5A above, but optionally replacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula YZ, any compound of Formula I can be prepared.

EXAMPLE 6 Preparation of a Compound of Formula (7) A. Preparation of aCompound of Formula (7) where R¹ and R² are n-Propyl and X is1,4-Phenylene

A solution of7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(4.39 g, 8.17 mmol) (prepared in a manner analogous to the preparationof the compound of formula (5)) in methylene chloride-methanol (1:1)(100 ml) was stirred under hydrogen with a catalytic amount of 10%Pd(OH)₂/C at room temperature overnight. The catalyst was filtered off,washed with dichloromethane/methanol, and the filtrate was evaporatedunder reduced pressure to give a solid, which was washed with methylenechloride to afford pure product,8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

A mixture of8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione (2.2.g,6.7 mmol), tert-butyldimethylsilyl chloride (2.0 g, 13.4 mmol), andimidazole (0.91 g, 13.4 mmol) in tetrahydrofuran (50 ml) was stirredovernight at room temperature, then refluxed for 10 hours. The solventwas removed under reduced pressure, and the residue was dissolved inmethylene chloride and passed through a silica gel plug, which was thenwashed with ethyl acetate. The filtrate was concentrated under reducedpressure to afford8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

To a solution of8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(13.7 g, 31 mmol) in tetrahydrofuran (200 ml) was added sodium hydride(1.6 g, 40 mmol), and the mixture was stirred for 30 minutes at roomtemperature. Benzyloxymethyl chloride (4.9 g, 31 mmol) was then added,and the mixture stirred for 1 hour at room temperature. The solvent wasthen removed under reduced pressure, and the residue dissolved inmethylene chloride. This solution was washed with brine, and the solventremoved under reduced pressure. The residue was chromatographed onsilica gel, eluting with ethyl acetate, to afford7-benzyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneas a liquid.

To a solution of7-benzyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(10.5 g, 18.7 mmol) in tetrahydrofuran (200 ml) was addedtetra(tert-butyl)ammonium fluoride (3 g), and the mixture stirred for 2hours at room temperature. The product was passed through a silica gelplug, which was washed with ethyl acetate. The filtrate was evaporatedunder reduced pressure, and the residue washed with dichloromethane, toafford7-benzyloxymethyl-8-(4-hydroxy-phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneas a white solid.

To a solution of7-benzyloxymethyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(Ig, 2.2 mmol) in tetrahydrofuran (20 ml) was added potassium t-butoxide(0.28 g, 2.4 mmol), and the mixture stirred for 30 minutes at roomtemperature. Todoacetonitrile (0.38 g, 2.23 mmol) was then added, andthe mixture stirred for 16 hours at room temperature. The solvent wasremoved under reduced pressure, and the residue was dissolved in ethylacetate and passed through a silica gel plug, to provide7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of formula (7)

B. Preparation of a Compound of Formula (7), Varying R¹ and R²

Similarly, following the procedure of 6A above, but replacing7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other similar compounds, other compounds of formula (7) areprepared.

EXAMPLE 7 Preparation of a Compound of Formula (8) A. Preparation of aCompound of Formula (8) where R¹ and R² are n-Propyl and X is1,4-Phenylene

A solution of7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.15 g, 2.36 mmol) in ethanol (50 ml) was stirred with sodium ethoxide(0.25 g, 3.54 mmol) and hydroxylamine hydrochloride (0.15 g, 3.54 mmol)at room temperature overnight. The solvent was removed under reducedpressure, the residue dissolved in dichloromethane/methanol (50:1), andthe solution passed through a silica gel plug. The filtrate wasevaporated under reduced pressure to afford8-[4-(2-amino-2-(hydroxyimino)ethoxy)phenyl]-7-[(phenylmethoxy)methyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula (8), Varying R¹ and R²

Similarly, following the procedure of 7A above, but replacing7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other similar compounds, other compounds of formula (8) areprepared.

EXAMPLE 8 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ and R² are n-Propyl, R³ is Hydrogen, X is1,4-Phenylene, Y is —O(CH₂)—, and Z is5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-yl

To a solution of7-benzyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg) in dioxane (3 ml) was added potassium carbonate (0.5 g),followed by 2-chlorobenzoyl chloride. The mixture was stirred at roomtemperature for 10 minutes, then the solids filtered off. The filtratewas evaporated under reduced pressure, and the residue dissolved inxylene. The solution was heated to 145° C. overnight, then the solventremoved under reduced pressure, and the residue chromatographed onsilica gel, eluting with ethyl acetate, to afford8-{4-[5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3-dihydropurine-2,6-dione.

B. Preparation of a Compound of Formula I where R¹ and R² are n-Propyl,Varying X, Y, and Z

Similarly, following the procedure of 8A above, but optionally replacing7-benzyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (8), and optionally replacing RC(O)Cl byother compounds of formula RC(O)Cl, the following compounds of Formula Iwere prepared:

-   8-(4-{[5-(3-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(2-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(2-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(3-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   methyl    4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;-   1,3-dipropyl-8-[4-({5-[2-(trifluoromethoxy)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   8-(4-{[5-(2,4-dimethoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

C.

Similarly, following the procedure of 8A above, but optionally replacing7-benzyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (8), and optionally replacing RC(O)Cl byother compounds of formula RC(O)Cl, other compounds of Formula I wereprepared, for example:

-   8-[1-(1-oxy-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.-   1,3-dipropyl-8-[1-(1-oxypyrid-4-ylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;    and-   1,3-dipropyl-8-[1-(1-oxypyrid-3-ylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 9A Preparation of a Compound of Formula I in which R¹ and R² arethe same A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl X is 1,4-Pyrazolene, R³ is Hydrogen, Y is Propylene, and Z isPhenyl

To a solution of ethyl 4-pyrazole carboxylate (3.57 mmol) in acetone (30ml) was added potassium carbonate (35.7 mmol) and1-bromo-3-phenylpropane (3.57 mmol). The suspension was refluxedovernight, after which the solvent was removed under reduced pressure.The residue was partitioned between ethyl acetate and water, the organiclayer dried over magnesium sulfate, filtered, and the filtrateevaporated under reduced pressure to give an oil, which was purified bypreparative TLC, to give ethyl 1-(3-phenylpropyl)pyrazole-4-carboxylate.

The ester was then dissolved in methanol (30 ml), and potassiumhydroxide (1.5 g) added. The mixture was refluxed for 5 hours undernitrogen, then the solvent removed under reduced pressure. The residuewas partitioned between methylene chloride and water. The aqueous layerwas separated and acidified to pH 1-2 with 6N hydrochloric acid, thenextracted with ethyl acetate. The combined organic layers were driedover magnesium sulfate, and the solvent removed under reduced pressure,to give 1-(3-phenylpropyl)pyrazole-4-carboxylic acid.

c To a solution of 1-(3-phenylpropyl)pyrazole-4-carboxylic acid (300 mg,1.30 mmol) in N,N-dimethylformamide (7 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (300 mg).The suspension was stirred at room temperature until all solid wasdissolved, then 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione(450 mg) added, and the reaction mixture stirred at room temperatureovernight. 2N sodium hydroxide (10 ml) was then added, and thesuspension heated at 120° C. for 2 hours. The reaction mixture wascooled in ice water and acidified to pH 2-3. The mixture was partitionedbetween water and ethyl acetate, and the ethyl acetate layer and anysolid material was washed with water, and the solvent removed underreduced pressure. The residue was triturated with ether, giving pureproduct,8-[1-(3-phenylpropyl)pyrazol-4-yl)]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 9B Alternative Preparation of a Compound of Formula I in whichR¹ and R² are the same A. Preparation of a Compound of Formula I whereR¹ and R² are n-Propyl, X is 1,4-Pyrazolene, R³ is Hydrogen, Y isMethylene, and Z is Phenyl

To a solution of 1-benzylpyrazole-4-carboxylic acid (4 g, 19.8 mmol) inN,N-dimethylformamide (80 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4 g). Thesuspension was stirred for 15 minutes at room temperature, then5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione (5.37 mg)added, and the reaction mixture stirred at room temperature overnight.The dimethylformamide was removed under reduced pressure, and 2N sodiumhydroxide (60 ml) was then added, and the suspension heated at 120° C.for 2 hours. The reaction mixture was cooled in ice water and acidifiedto pH 1-2. The mixture was partitioned between water and ethyl acetate,the ethyl acetate layer and accompanying solid was washed several timeswith water, and the solvent removed under reduced pressure. The residuewas triturated with ether, giving8-[1-benzylpyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

8-[1-benzylpyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(3.88 g) was dissolved in dimethylformamide (30 ml), and potassiumcarbonate (0.642 g) was added, followed by2-(trimethylsilyl)ethoxymethyl chloride (SEM chloride, 0.768 g). Thesuspension was stirred at room temperature overnight, at which time afurther 0.4 equivalents of potassium carbonate and SEM chloride wereadded, and the mixture stirred for a further 3 hours. The solid wasfiltered off, and solvent removed from the filtrate under reducedpressure. The residue was chromatographed on a silica gel column,eluting with 20% ethyl acetate/hexanes, to yield7-[(3,3-dimethyl-3-silabutoxy)methyl]-8-[1-benzylpyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

To a solution of7-[(3,3-dimethyl-3-silabutoxy)methyl]-8-[1-benzylpyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(3 g) in ethanol (100 ml) was added cyclohexene (50 ml) and palladiumhydroxide (3 g). The mixture was refluxed for 4 days, then the catalystwas filtered off, and solvent removed from the filtrate under reducedpressure. The residue was chromatographed on a silica gel column,eluting with 30% ethyl acetate/hexanes, to yield7-[(3,3-dimethyl-3-silabutoxy)methyl]-1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.

To a solution of7-[(3,3-dimethyl-3-silabutoxy)methyl]-1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione(50 mg) in dimethylformamide (2 ml) was added bromoethylbenzene (0.16ml) and potassium carbonate (159 mg). The mixture was stirred at roomtemperature overnight, and the solid material filtered off. Solvent wasremoved from the filtrate under reduced pressure, and the residue waschromatographed by preparative thin layer chromatography, eluting with30% ethyl acetate/hexanes, to yield7-[(3,3-dimethyl-3-silabutoxy)methyl]-8-[1-(2-phenylethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

A solution of7-[(3,3-dimethyl-3-silabutoxy)methyl]-8-[1-(2-phenylethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(53 mg) in ethanol/hydrochloric acid (1M, 2 ml) was refluxed for 2hours. Solvent was removed from the product under reduced pressure, andthe residue was washed with ether, to provide8-[1-(2-phenylethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula I where R¹ and R² are the Same,Varying X, Y, and Z

Similarly, following the procedure of Example 9A and/or 9B above, thefollowing compounds of Formula I were prepared:

-   8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3,5-dimethylisoxazol-4-yl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-[1-(3-cyclohexylpropyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(2-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-[1-(2-phenoxyethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   N-(2,6-dimethylphenyl)-2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]acetamide;-   8-(1-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[2-(1,3-dioxobenzo[c]azolin-2-yl)ethyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-(2-chlorophenyl)acetamide;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-phenylacetamide;-   8-{1-[(2-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[2-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[4-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   2-[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]acetic    acid;-   8-[1-(2-hydroxyethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic    acid;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-(4-fluorophenyl)acetic    acid;-   2-[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]propanoic    acid;-   8-[1-(phenylethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-[1-(4-chlorophenyl)-5-(trifluoromethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-[1-phenyl-5-(trifluoromethyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-phenyl-5-propylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(5-methyl-1-phenylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   ethyl    2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetate;-   1,3-dimethyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-phenylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1,3-dimethylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-ethyl-3-methylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dibutyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dibutyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1,3-dimethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-diethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-di-(sec-butyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-di(sec-butyl)-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-di(sec-butyl)-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(2,5-dichlorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-diethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-diethyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;    and-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic    acid;-   1,3-diethyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.-   8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(5-phenyl(1,2,4-oxadiazol-3-yl))methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(5-phenylisoxazol-3-yl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(2-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(6-chloro-2-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2,3-difluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2,4-difluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2,6-difluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3,4-difluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[4-methoxy-3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[3,5-bis(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-phenylisoxazol-5-yl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-({2-[4-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(2,4-difluorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(2,4,6-trifluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-chloro-2-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-fluoro-3-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[2-chloro-5-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-({5-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-(4-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-[1-(3-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-[1-((1R)indanyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-[1-((1S)indanyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   methyl    3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}-benzoate;-   3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}benzoic    acid;-   1,3-dipropyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(6-chloro(3-pyridyl))methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-{1-[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   4-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}benzene-carbonitrile;-   8-{1-[(4-methoxy-3,5-dimethyl(2-pyridyl))methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3,4-dimethoxy(2-pyridyl))methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(5-chloro(2-thienyl))methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   6-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}pyridine-2-carboxylic    acid.

C. Preparation of a Compound of Formula I where R¹ and R² are the Same,Varying X, Y, and Z

Similarly, following the procedure of Example 9A and/or 9B above, othercompounds of Formula I are prepared:

EXAMPLE 10 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ and R² are n-Propyl, X is 1,4-Pyrazolene,R³ is 2-Hydroxyethyl, Y is Methylene, and Z is Phenyl

To a solution of8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(0.51 mmol) in N,N-dimethylformamide (2 ml) was added potassiumcarbonate (5.1 mmol) and 2-bromoethanol (5.1 mmol). The suspension washeated at 70° C. overnight, the solvent removed under reduced pressure,and the residue purified by preparative TLC, yielding pure7-(2-hydroxyethyl)-8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula I where R¹ and R² are n-Propyl,Varying X, Y, and Z

Similarly, following the procedure of 10A above, but replacing2-bromoethanol with other compounds of formula R³LG, the followingcompounds of Formula I were prepared:

-   7-allyl-8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   7-(methylethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   7-(2-methoxyethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   7-methyl-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   7-(prop-2-enyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.    C. Preparation of a Compound of Formula I where R¹ and R² are    n-Propyl, Varying X, Y, and Z

Similarly, following the procedure of 10A above, but replacing2-bromoethanol with other compounds of formula R³LG, other compounds ofFormula I are prepared:

EXAMPLE 11 Preparation of a Compound of Formula (22) A. Preparation of aCompound of Formula HO—C(O)—XYZ in which X is Phenyl Y is —O—CH₂—, and Zis 5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

A solution of methyl 4-hydroxybenzoate (3.04 g, 20 mmol) and3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole (4.48 g, 20 mmol)in acetone (200 ml) was refluxed overnight. The mixture was filtered,solvent removed from the filtrate, and the residue was dissolved inethyl acetate. Methanol was added to this solution to precipitate theproduct, methyl4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate.

A solution of methyl4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate (5.0 g)and potassium hydroxide (10 g) in methanol (200 ml) was refluxed for 4.5hours. The solvent was removed under reduced pressure, and the residuepartitioned between methylene chloride and water. The aqueous layer wasacidified with 6N hydrochloric acid to pH 3, and the precipitateextracted into ethyl acetate. The solvent was removed under reducedpressure to give4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid.

B. Preparation of a Compound of Formula HO—C(O)—XYZ, Varying X, Y and Z

Similarly, following the procedure of 11A above, but replacing3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole with other3-chloromethyl-5-substituted-[1,2,4]oxadiazoles, the following compoundsof formula HO—C(O)—XYZ I were prepared:

-   4-{2-[5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid;-   4-{2-[5-cyclopentyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid; and-   4-{2-[5-cyclohexyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid.

C. Preparation of a Compound of Formula HO—C(O)—XYZ, Varying X, Y, and Z

Similarly, following the procedure of 11A above, but replacing3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole with other3-chloromethyl-5-substituted-[1,2,4]oxadiazoles, other compounds offormula HO—C(O)—XYZ I are prepared:

EXAMPLE 12 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ and R² are n-Propyl R³ is Hydrogen, X is1,4-Phenylene, Y is —O(CH₂)— and Z is5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

A mixture of4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid (3.0g), 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione (3.2 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.0 g) inN,N-dimethyl-formamide (50 ml) was stirred overnight at roomtemperature. The solvent was removed under reduced pressure, and theresidue dried under vacuum for 1 hour. To this was added 150 ml of 2Nsodium hydroxide, and the mixture was heated at 120° C. for 2 hours.

The mixture was cooled to 0° C., and acidified with 6N hydrochloric acidto pH 2-3. The mixture was partitioned between water and ethyl acetate,and the ethyl acetate layer separated along with some solid product.This mixture was washed with water, solvent removed from the organiclayer to a volume of about 20 ml. The solid thus obtained was filteredoff, washed with ethyl acetate, and once with ethyl acetate/methanol(1:1). The solid was dried under vacuum to provide8-{4-[5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of Formula I.

B. Preparation of a Compound of Formula I where R¹ and R² are n-Propyl,Varying X, Y, and Z

Similarly, following the procedure of 12A above, but optionallyreplacing 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoicacid with other compounds of formula (22), and optionally replacing5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione with similarcompounds, the following compounds of Formula I were prepared:

-   8-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[2-phenoxyethoxy)phenyl-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-fluorophenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(3-cyclohexyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(3-cyclopentyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[3-(3-chlorophenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[3-(4-biphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[3-(4-isopropylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[3-(4-tert-butylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-iodopyrazol-1-yl)ethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[3-(4-methylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   8-{4-[3,5-dimethyl-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.    C. Preparation of a Compound of Formula I where R¹ and R² are    n-Propyl, Varying X, Y, and Z

Similarly, following the procedure of 12A above, but optionallyreplacing 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoicacid with other compounds of formula (22), and optionally replacing5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione with othersimilar compounds, other compounds of Formula I are prepared.

EXAMPLE 13 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ and R² are n-Propyl, R³ is Hydrogen, X is1,4-Phenylene, Y is —O(CH₂)— and Z is5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

To a solution of8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(3.8 g, 9.08 mmoles) in anhydrous dimethylformamide (100 mL) was addedpotassium carbonate (6.27 g, 45.4 mmoles), followed by2-(trimethylsilyl)ethoxymethyl chloride (3.2 mL, 18 mmoles), and themixture stirred at 70° C. for 72 hours. The solvent was removed underreduced pressure, and the residue purified by flash columnchromatography, eluting with 30% EtOAc/Hexanes, to give 3.7 g of7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.74 g, 3.17 mmoles) was dissolved in methanol (100 mL), and to it wasadded Pearlmann's catalyst (1.0 g). The resulting suspension was stirredat room temperature under a positive hydrogen pressure for 16 hours. Thesuspension was filtered through celite, washed several times with 50:50methylene chloride:methanol, and the filtrate was evaporated to give7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.2 g) as a white solid.

7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg, 0.1 mmoles) was dissolved in acetone (2.5 mL), to which wasadded potassium carbonate (0.5 g), followed by 5-chloromethyl3-[(4-chloro)phenyl]oxadiazole (25 mg, 0.1 mmoles), and the mixture wasstirred at 60 deg C. for 16 hours. The solvent was removed under reducedpressure, and evaporated and the residue was subjected to preparativethin layer chromatography, eluting with 30% EtOAc/Hexanes, to provide7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg).

7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewas dissolved in ethanol (2 mL), to which was added 1M HCL (0.5 mL). Themixture was refluxed for 2 hours. The resulting white residue wascollected by evaporating the solvent under reduced pressure and washingthe residue with ethanol (3×2 mL), to give pure8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

B. Preparation of a Compound of Formula I where R¹ and R² are n-Propyl,Varying X, Y and Z

Similarly, following the procedure of 13A above, but replacing5-chloromethyl 3-[(4-chloro)phenyl]oxadiazole with similar compounds,the following compounds of Formula I were prepared:

-   8-(4-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[2-(4-iodopyrazolyl)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[2-(4-methylpyrazolyl)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(2-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   N-(2,6-dimethylphenyl)-2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]acetamide;-   8-(1-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[2-(1,3-dioxoisoindolin-2-yl)ethyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-(2-chlorophenyl)acetamide;-   2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-phenylacetamide;-   1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   methyl    4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;-   1,3-dipropyl-8-[4-({5-[2-(trifluoromethoxy)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-(4-{[5-(2,4-dimethoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[2-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione-   8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   1,3-dipropyl-8-(1-{[4-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(4-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;    and-   8-{1-[(4-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.    C. Preparation of a Compound of Formula I where R¹ and R² are    n-Propyl, Varying X, Y and Z

Similarly, following the procedure of 13A above, but replacing5-chloromethyl 3-[(4-chloro)phenyl]oxadiazole with similar compounds,other following compounds of Formula I are prepared:

EXAMPLE 14 Preparation of a Compound of Formula (23) A. Preparation of aCompound of Formula (23) in which R¹ is n-Butyl

A mixture of 6-aminouracil (5 g, 10 mmol), hexamethyldisilazane (40 ml),and ammonium sulfate (260 mg, 1.97 mmol) was refluxed for 4 hours.Excess HMDS was removed under reduced pressure to provide thetrimethylsilylated derivative of 6-aminouracil.

The product was combined with 1-iodobutane (10 ml) and heated in an oilbath at 130° C. for 3 days. The reaction mixture was then cooled to 0°C., and saturated aqueous sodium bicarbonate added. The resultingprecipitate was filtered off, washed with water, to provide6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula(23), which was used in the next reaction with no further purification.

B. Preparation of Other Compounds of Formula (23)

Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, the followingcompounds of formula (23) were prepared:

-   6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and-   6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (23)

Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, the followingcompounds of formula (23) are prepared.

-   6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (23)

Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, other compounds offormula (23) are prepared.

EXAMPLE 15 Preparation of a Compound of Formula (24) A. Preparation of aCompound of Formula (24) in which R¹ is n-Butyl

A mixture of 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (4.0 g,21.8 mmol) and aqueous acetic acid (120 ml) was heated at 70° C. untilcomplete solution as attained, and the solution was cooled to 30° C.Sodium nitrite (3 g) was added in small portions while stirring, formingan orange precipitate. The reaction mixture was cooled to 0° C., and theprecipitate filtered off, washed with water, and dried under reducedpressure, to provide5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, which wasused in the next reaction with no further purification.

B. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (23), the following compounds of formula (24) were prepared:

-   5-nitroso-6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and-   5-nitroso-6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other halides offormula (23), the following compounds of formula (24) are prepared.

-   5-nitroso-6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   5-nitroso-6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   5-nitroso-6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other halides offormula (23), other compounds of formula (24) are prepared.

EXAMPLE 16 Preparation of a Compound of Formula (25) A. Preparation of aCompound of Formula (25) in which R¹ is n-Butyl

A mixture of 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione(2.1 g, 10 mmol) and aqueous ammonia (50 ml) was heated at 70° C. untilcomplete solution as attained. Sodium hydrosulfite (7 g) was then addedin small portions until the solution became clear and colorless. Thereaction mixture was evaporated under reduced pressure until crystalsappeared, and was then cooled to 0° C. The precipitate filtered off,washed with cold water,5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione, a compound offormula (25), which was used in the next reaction with no furtherpurification.

B. Preparation of Other Compounds of Formula (25)

Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), the following compounds of formula (25) wereprepared:

-   5,6-diamino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and-   5,6-diamino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (25)

Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), the following compounds of formula (24) areprepared.

-   5,6-diamino-3-methyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   5-nitroso-6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (25)

Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), other compounds of formula (24) are prepared,for example8-[1-(1-oxy-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.

EXAMPLE 17 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ is n-Butyl R² is Hydrogen, R³ isHydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Z is Phenyl

To a mixture of 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione (1.2g, 6 mmol) and 1-benzylpyrazole-4-carboxylic acid (1.2 g, 6 mmol) inmethanol (30 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.16 g, 6 mmol). A bright yellow solid precipitated. Themixture was stirred overnight at room temperature, and the solidfiltered off, washed with methanol, and dried under reduced pressure.The product was combined with hexamethyldisilazane (50 ml) and ammoniumsulfate (18 mg) and heated at 130° C. for 48 hours. The solvent was thenremoved under reduced pressure, and the residue triturated with methanolwater (1:1), to provide1-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione, acompound of Formula I.

B. Preparation of Other Compounds of Formula I

Similarly, following the procedure of 17A above, but replacing5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compoundsof formula (25), the following compounds of Formula I were prepared:

-   1-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-butyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-butyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-butyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione);-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-ethynyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-ethynyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-benzyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-(1-{[3-trifluoromethylphenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-{1-[(5-phenylisoxazol-3-yl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-(2-methylpropyl)-8-[1-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(2,5-dichlorophenyl)methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(3,4-difluorophenyl)methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione;-   3-{[4-(2,6-dioxo-1-propyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}benzoic    acid;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-(cyclopropylmethyl)-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-8-[1-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-n-butyl-8-[1-(6-trifluoromethylpyridin-3-ylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1-(cyclopropylmethyl)-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[2-chloro-5-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-{1-[(5-phenylisoxazol-3-yl)methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;-   1-propyl-8-[1-({5-[4-(trifluoromethyl)phenyl]    (1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;    and-   8-{1-[(5-phenyl(1,2,4-oxadiazol-3-yl))methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione.

C. Preparation of Other Compounds of Formula I

Similarly, following the procedure of 17A above, but optionallyreplacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (25), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),the following compounds of Formula I are prepared.

-   1-methyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-isopropyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-n-pentyl-8-(1-{[3-chlorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(3-propylpentyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(2-phenylethyl)-8-[1-{benzyl}pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-(2-methoxyethyl)-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(3-hydroxypropyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(4-fluorobutyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(2-ethylcarboxyethyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-ethenyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-cyclopentyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(3-hydroxycyclopentyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-cyclohexyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-phenyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(pyrid-3-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(pyrid-3-ylmethyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-(tetrahydrofuran-3-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;    and-   1-(piperidin-4-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.

D. Preparation of Other Compounds of Formula I

Similarly, following the procedure of 17A above, but optionallyreplacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (25), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),other compounds of Formula I are prepared.

EXAMPLE 18 Preparation of a Compound of Formula (31) A. Preparation of aCompound of Formula (31) in which R is Benzyl

A solution of sodium ethoxide was prepared from sodium (1.53 g, 67 mmol)and dry ethanol (75 ml). To this solution was added benzyl urea (5.0 g,33 mmol) and ethyl cyanoacetate (3.77 g, 33 mmol). This reaction mixturewas stirred at reflux for 10 hours, cooled, and the precipitate filteredoff and washed with ethanol. The precipitate was dissolved in water, andthe pH adjusted to between 5 and 6 with hydrochloric acid. The solidmaterial was filtered off, washed with water and dried under vacuum, toprovide 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound offormula (31), which was used in the next reaction with no furtherpurification.

B. Preparation of Other Compounds of Formula (31)

Similarly, following the procedure of 18A above, but replacing benzylurea with other compounds of formula (30), the following compounds offormula (31) were prepared:

-   6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and-   6-amino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (31)

Similarly, following the procedure of 18A above, but replacing benzylurea with other compounds of formula (30), other compounds of formula(31) are prepared.

-   6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   6-amino-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (31)

Similarly, following the procedure of 18A above, but replacing benzylurea with other compounds of formula (30), other compounds of formula(31) are prepared.

EXAMPLE 19 Preparation of a Compound of Formula (24) A. Preparation of aCompound of Formula (24) in which R² is Benzyl

To a solution of 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (2.0g, 9.2 mmol) in a mixture of 15 ml of N,N-dimethylformamide and 5 ml ofwater at 90° C. was added sodium nitrite (1.27 g, 69 mmol). To thisreaction mixture was added concentrated hydrochloric acid until therewas no deepening of color, and the mixture was heated at 70° C. for 1hour. The solvent was removed under reduced pressure, the residuedissolved in water, and concentrated hydrochloric acid added to producea pH of 4.0. The precipitate was filtered off, washed with water, anddried under reduced pressure, to provide6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compoundof formula (24).

B. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), the following compounds of formula (24) were prepared:

-   6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and-   6-amino-5-nitroso-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), the following compounds of formula (24) are prepared.

-   6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-phenyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-5-nitroso-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   6-amino-5-nitroso-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (24)

Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), other compounds of formula (24) are prepared.

EXAMPLE 20 Preparation of a Compound of Formula (21) A. Preparation of aCompound of Formula (21) in which R is Benzyl

To a solution of6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione (1.15 g, 4.7mmol) in 12.5% aqueous ammonia (40 ml) at 70° C. was added sodiumhydrosulfite (2.44 g, 14 mmol) in portions over 15 minutes. On coolingthe reaction mixture in an ice bath the product precipitated out. It wasfiltered, washed with water, and dried under reduced pressure, toprovide 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compoundof formula (21).

B. Preparation of Other Compounds of Formula (21)

Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), the following compounds of formula (21) wereprepared:

-   5,6-diamino 1-methyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino 1-n-propyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and-   5,6-diamino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Other Compounds of Formula (21)

Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), the following compounds of formula (21) areprepared.

-   5,6-diamino-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;-   5,6-diamino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;    and-   5,6-diamino-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Preparation of Other Compounds of Formula (21)

Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), other compounds of formula (21) are prepared.

EXAMPLE 21 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ is Hydrogen, R² is Benzyl R³ is Hydrogen,X is 1,4-Pyrazolene, Y is Methylene, and Z is Phenyl

A solution of 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (200mg, 0.8 mmol), 1-benzylpyrazole-4-carboxylic acid (202 mg, 1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1mmol) was dissolved in N,N-dimethylformamide and stirred for 16 hours.Solvent was then removed under reduced pressure, and the residuedissolved in hexamethyldisilazane (HMDS). To this solution was addedammonium sulfate, and the mixture was heated at 125° C. for 80 hours.Excess HMDS was removed under reduced pressure, and the residue slurriedwith a mixture of 1:1 methanol and water. The solid was filtered off,washed with 1:1 methanol and water, and dried under reduced pressure, toprovide3-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione, acompound of Formula I.

B. Preparation of a Compound of Formula I where R¹ is Hydrogen, R³ isHydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Z is Phenyl,Varying R²

Similarly, following the procedure of 21A above, but replacing5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (21), the following compounds of Formula I wereprepared:

-   3-n-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-isobutyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-n-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-(2-methylpropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;    and-   3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

C. Preparation of a Compound of Formula I where R¹ is Hydrogen, VaryingR², R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Z isPhenyl

Similarly, following the procedure of 21A above, but optionallyreplacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione withother compounds of formula (21), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),the following compounds of Formula I are prepared.

-   3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-isopropyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-n-pentyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(1-propylpentyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(2-phenyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(2-methoxyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(3-hydroxypropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(4-fluorobutyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(2-ethylcarboxyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-ethenyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-cyclopentyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(3-hydroxycyclopentyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-cyclohexyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-cyclopropylmethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-phenyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(pyrid-3-yl)n-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(pyrid-3-ylmethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.-   3-(tetrahydrofuran-3-yl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;    and-   3-(piperidin-4-yl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.    D. Preparation of a Compound of Formula I where R¹ is Hydrogen,    Varying R², R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene    and Z is Phenyl

Similarly, following the procedure of 21A above, but optionallyreplacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione withother compounds of formula (21), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),other compounds of Formula I are prepared.

EXAMPLE 22 Preparation of a Compound of Formula (33) A. Preparation of aCompound of Formula (33) in which R¹ is n-Butyl and R² is Methyl

A suspension of 6-amino-1-methyl uracil (3.0 g) in anhydrousN,N-dimethylformamide dimethylacetal (10 ml) and N,N-dimethylacetamide(50 ml) was warmed at 40° C. until the disappearance of startingmaterial was observed (60 min). Potassium carbonate (10 g) and n-butylbromide (7.8 g) were then added, and the reaction mixture was stirred at80° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered, the solvents were evaporated and the product offormula (33),6-[1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione,was used as such for the next reaction.

B. Preparation of Compounds of Formula (33), Varying R¹ and R²

Similarly, following the procedure of 22A above, but optionallyreplacing 6-amino-1-methyluracil with other compounds of formula (31),and optionally replacing n-butyl bromide with other alkyl halides, thefollowing compounds of formula (33) were prepared:

-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-prop-2-ynyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-butyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl 3-sec    butyl-1,3-dihydropyrimidine-2,4-dione; and    6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-n    butyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Compounds of Formula (33), Varying R¹ and R²

Similarly, following the procedure of 22A above, but optionallyreplacing 6-amino-1-methyluracil with other compounds of formula (31),and optionally replacing n-butyl bromide with other alkyl halides, othercompounds of formula (33) are prepared.

EXAMPLE 23 Preparation of a Compound of Formula (34) A. Preparation of aCompound of Formula (34) in which R¹ is n-Butyl and R² is Methyl

The6-[(1E)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione(4.0 g) obtained in Example 22A was suspended in methanol. To thissuspension was added aqueous ammonium hydroxide, and the reactionmixture was stirred at room temperature for 48 hours. After startingmaterial was no longer observed, the solvents were removed under reducedpressure, the residue was suspended in water, and the precipitate wasfiltered, washed with water, and dried under reduced pressure, toprovide crude 6-amino-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione,which was used as such in the next reaction.

B. Preparation of Compounds of Formula (34), Varying R¹ and R²

Similarly, following the procedure of 23A above, but replacing6-[(1E)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dionewith other compounds of formula (33), the following compounds of formula(34) were prepared:

-   6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-ethyl-3-(prop-2-ynyl)-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-methyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;-   6-amino-1-ethyl 3-sec butyl-1,3-dihydropyrimidine-2,4-dione; and-   6-amino-1-ethyl-3-n butyl-1,3-dihydropyrimidine-2,4-dione.

C. Preparation of Compounds of Formula (34), Varying R¹ and R²

Similarly, following the procedure of 23A above, but replacing6-[(1E)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dionewith other compounds of formula (33), other compounds of formula (34)are prepared.

EXAMPLE 24 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I where R¹ is n-Butyl R² is Methyl, X is1,4-Pyrazolene, Y is Methylene, and Z is 3-Fluorophenyl

The compound of formula (34) is then converted into a compound ofFormula I in the same manner as shown for the conversion of a compoundof formula (23) in Examples 14, 15, 16, and 17. That is, reaction withsodium nitrite to a 5-nitroso-6-amino derivative, which is reduced to a5,6-diamino derivative, which in turn is reacted with an appropriatelysubstituted carboxylic acid of formula Z-Y—X—CO₂H to provide a compoundof Formula I. In this manner, the following compounds were prepared:

-   1-butyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   3-methyl-1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-(prop-2-ynyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-ethyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   ethyl    2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetate;-   1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-methyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-methyl-1-propyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-ethyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-butyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-butyl-3-methyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-ethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-methyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-sec-butyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-cyclopropylmethyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.-   1-butyl-3-methyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-(2-methylpropyl)-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-3-methyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;-   1-ethyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-[1-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione;-   8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione;-   3-({4-[1-(cyclopropylmethyl)-3-methyl-2,6-dioxo-1,3,7-trihydropurin-8-yl]pyrazolyl}methyl)benzenecarbonitrile;-   8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-8-{1-[(5-phenylisoxazol-3-yl)methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-propyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   3-{[4-(3-ethyl-2,6-dioxo-1-propyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}-benzenecarbonitrile;-   3-ethyl-1-propyl-8-{1-[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-8-{1-[(6-methyl(3-pyridyl))methyl]pyrazol-4-yl}-1-propyl-1,3,7-trihydropurine-2,6-dione;-   1-(cyclopropylmethyl)-3-ethyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;-   3-ethyl-1-(2-methylpropyl)-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;    and-   8-[1-(2-(1H-1,2,3,4-tetraazol-5-yl)ethyl)pyrazol-4-yl]-1-(cyclopropylmethyl)-3-methyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 25

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 26

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

EXAMPLE 27

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

EXAMPLE 28

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 29

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 30

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

EXAMPLE 31

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 32

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP 50 mg/mlGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF q.s.

EXAMPLE 33

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60⁾ C with stirring. A sufficient quantity of water at 60⁾ C is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

EXAMPLE 34

Sustained Release Composition Weight Preferred Ingredient Range (%)Range (%) Most Preferred Active ingredient 50-95 70-90 75Microcrystalline cellulose (filler)  1-35  5-15 10.6 Methacrylic acidcopolymer  1-35   5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate 0.5-5.01-3 2.0

The sustained release formulations of this invention are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropyl.methylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers-Eudragit® E-Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

EXAMPLE 35 A_(2B) Adenosine Receptor Assays Methods Radioligand Bindingfor A_(2B) Adenosine Receptor.

Human A_(2B) adenosine receptor cDNA was stably transfected into HEK-293cells (referred to as HEK-A2B cells). Monolayer of HEK-A2B cells werewashed with PBS once and harvested in a buffer containing 10 mM HEPES(pH 7.4), 10 mM EDTA and protease inhibitors. These cells werehomogenized in polytron for 1 minute at setting 4 and centrifuged at29000 g for 15 minutes at 4° C. The cell pellets were washed once with abuffer containing 10 mM HEPES (pH7.4), 1 mM EDTA and proteaseinhibitors, and were resuspended in the same buffer supplemented with10% sucrose. Frozen aliquots were kept at −80° C. Competition assayswere started by mixing 10 nM ³H-ZM214385 (Tocris Cookson) with variousconcentrations of test compounds and 50 μg membrane proteins in TEbuffer (50 mM Tris and 1 mM EDTA) supplemented with 1 Unit/mL adenosinedeaminase. The assays were incubated for 90 minutes, stopped byfiltration using Packard Harvester and washed four times with ice-coldTM buffer (10 mM Tris, 1 mM MgCl2, pH 7.4). Non specific binding wasdetermined in the presence of 10 μM ZM214385. The affinities ofcompounds (i.e. Ki values) were calculated using GraphPad software.

Radioligand Binding for Other Adenosine Receptors.

Human A₁, A_(2A), A₃ adenosine receptor cDNAs were stably transfectedinto either CHO or HEK-293 cells (referred to as CHO-A1, HEK-A2A,CHO-A3). Membranes were prepared from these cells using the sameprotocol as described above. Competition assays were started by mixing0.5 nM ³H—CPX (for CHO-A1), 2 nM ³H-ZM214385 (HEK-A2A) or 0.1 nM¹²⁵I-AB-MECA (CHO-A3) with various concentrations of test compounds andthe perspective membranes in TE buffer (50 mM Tris and 1 mM EDTA foCHO-A1 and HEK-A2A) or TEM buffer (50 mM Tris, 1 mM EDTA and 10 mM MgCl₂for CHO-A3) supplemented with 1 Unit/mL adenosine deaminase. The assayswere incubated for 90 minutes, stopped by filtration using PackardHarvester and washed four times with ice-cold TM buffer (10 mM Tris, 1mM MgCl₂, pH 7.4). Non specific binding was determined in the presenceof 1 μM CPX (CHO-A1), 1 μM ZM214385 (HEK-A2A) and 1 μM IB-MECA (CHO-A3).The affinities of compounds (i.e. Ki values) were calculated usingGraphPad software.

cAMP measurements.

Monolayer of transfected cells were collected in PBS containing 5 mMEDTA. Cells were washed once with DMEM and resuspended in DMEMcontaining 1 Unit/mL adenosine deaminase at a density of 100,000-500,000cells/ml. 100 μl of the cell suspension was mixed with 25 μl containingvarious agonists and/or antagonists and the reaction was kept at 37° C.for 15 minutes. At the end of 15 minutes, 125 μl 0.2N HCl was added tostop the reaction. Cells were centrifuged for 10 minutes at 1000 rpm.100 μl of the supernatant was removed and acetylated. The concentrationsof cAMP in the supernatants were measured using the direct cAMP assayfrom Assay Design.

A_(2A) and A_(2B) adenosine receptors are coupled to Gs proteins andthus agonists for A_(2A) adenosine receptor (such as CGS21680) or forA_(2B) adenosine receptor (such as NECA) increase the cAMP accumulationswhereas the antagonists to these receptors prevent the increase in cAMPaccumulations-induced by the agonists. A₁ and A₃ adenosine receptors arecoupled to Gi proteins and thus agonists for A₁ adenosine receptor (suchas CPA) or for A₃ adenosine receptor (such as IB-MECA) inhibit theincrease in cAMP accumulations-induced by forskolin. Antagonists to A₁and A₃ receptors prevent the inhibition in cAMP accumulations.

The compounds of the invention were shown to be A_(2B)-antagonists bythe above tests.

Compounds of the invention were also tested in a mouse model for asthma,using the procedures disclosed in U.S. Pat. No. 6,387,913, the relevantportion of which is hereby incorporated by reference, and shown to beefficacious.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dioneand a pharmaceutically acceptable carrier.
 2. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition is forintravenous administration.
 3. The pharmaceutical composition of claim1, wherein the pharmaceutical composition is in the form of a singledosage unit.
 4. The pharmaceutical composition of claim 3, wherein thesingle dosage unit is for oral administration.
 5. The pharmaceuticalcomposition of claim 4, wherein the single dosage unit is in the form ofa table, capsule, or hard or soft gelatin capsule.
 6. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition is fortopical administration.
 7. The pharmaceutical composition of claim 1,wherein the pharmaceutical composition is for intramuscularadministration.
 8. The pharmaceutical composition of claim 1, whereinthe pharmaceutical composition is for intraperitoneal administration. 9.The pharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition is for inhalation.
 10. The pharmaceutical composition ofclaim 1, wherein the pharmaceutical composition is formulated to providequick, sustained or delayed release of the3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.11. The pharmaceutical composition of claim 4, wherein the single dosageunit contains approximately 10 mg to 2 g of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.12. The pharmaceutical composition of claim 11, wherein the singledosage unit contains approximately 10 mg to 700 mg of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.13. The pharmaceutical composition of claim 12, wherein the singledosage unit contains approximately 50 mg to 200 mg of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.14. A pharmaceutical composition comprising a therapeutically effectiveamount of a pharmaceutically acceptable salt or ester of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dioneand a pharmaceutically acceptable carrier.
 15. The pharmaceuticalcomposition of claim 14, wherein the pharmaceutical compositioncomprises a pharmaceutically acceptable salt of3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.16. The pharmaceutical composition of claim 14, wherein thepharmaceutical composition comprises a pharmaceutically acceptable esterof3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.